Marijuana (Cannabis sativa) is the most commonly used illicit drug by pregnant women in western societies. The major psychoactive component in cannabis is delta-9-tetrahydrocannabinol (THC), which readily crosses the placenta and can affect the fetus. Human longitudinal studies have documented specific long-term abnormalities in cognitive and behavioral function in offspring of women who used marijuana during pregnancy. Despite the large number of cannabis-exposed infants born each year and the documented behavioral impairments in such individuals, there is still no knowledge about the specific neurobiological consequences of prenatal cannabis exposure in humans. The neural actions of THC are mediated predominantly via the cannabinoid receptor type-1 (CB1) subtype. In the adult brain, there is a strong anatomical and functional interaction between the CB1 and endogenous dopamine (DA) and opioid neuropeptide (e.g., enkephalin and dynorphin) systems, substrates involved in various neural functions including reward, emotional regulation, motor behavior, and cognition. We have established a Human Fetal Brain Bank and recently observed that the CB1 gene is predominantly expressed in mesocorticolimbic areas such as the amygdala and hippocampus in the midgestation (week 17-22) human fetal brain. We also revealed evidence of mesolimbic DAergic abnormality (reduced D2 receptor mRNA expression) in the amygdala of the fetuses exposed in utero to cannabis; the effects were most pronounced in males. We propose to continue our investigations to characterize specific regional alterations of DA and opioid peptide-related genes in the striatum and amygdala of midgestation human fetuses exposed prenatally to cannabis. Experiments will also be carded out to assess the extent to which changes in mRNA expression are correlated to corresponding protein products. Additionally, an experimental prenatal cannabis rat model will be developed to mimic the neural alterations evident in the human fetal brain so that long-term behavioral and in vivo DAergic alterations can be evaluated in the adult offspring. In spite of the difficult challenges to study the human fetal brain, such investigations are critical in order to expand our limited understanding about drug effect on human neurodevelopment and also to expand our knowledge about normal human neurodevelopment.